Genetic Map of Chromosome 7 AUS1 Families

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Why Genetics?

• To understand the disease
• To define subgroups of the disease
• To identify individuals at risk and prevent
  disease
• To define new targets for treatment

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Why Genetic Epidemiology?

• Current state of knowledge inadequate
• Many polymorphisms
• Many inconclusive results
• Small select samples
• Population-based studies
• Large samples
• Disease subtypes
• Gene-gene interaction
• Gene-environment interaction

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Genetic Epidemiology

• Disease
• Intermediate phenotypes
• Genetic polymorphism
• Environmental factors

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Genetic Epidemiology

• Multiple genes
• Gene gene interaction
• Additive (A B C)
• Multiplicative (A x B x C)
• Independent (A or B or C)
• Many environmental factors
• Gene environment interaction
• Current effects
• Past effects selection

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Known Genetic Effects on Atopy

• HLA Class II
• FceRI-b
• TNF
• CD14
• TCR-a
• IL13
• IL4-R
• SPINK5

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Key Linkage Regions

• Chromosome 2 gene ID
• Chromosome 4 gene ID
• Chromosome 5 candidates
• Chromosome 6 candidates
• Chromosome 7 gene ID
• Chromosome 11 candidates
• Chromosome 12 gene ID
• Chromosome 13 gene ID
• Chromosome 16 candidates

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MHC
CLASS II CLASS III CLASS I
DP DQ DR C4 C2 Bf TNF
B C A
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• Kalumburu

• Busselton

The Land of OZ

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Kimberly Aborigines

• North-west Australia
• Heavily infested with hookworm
• IgE levels 40 times higher than in Caucasians
• 60 are house dust mite sensitive

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Aborigines Skin Tests, Specific and Total IgE
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HLA-DR allele frequencies

• Caucasians
• HLA-DRB101 8
• HLA-DRB11501 14
• HLA-DRB103 14
• HLA-DRB104 20
• HLA-DRB107 15

• Aborigines
• HLA-DRB11502 13
• HLA-DRB104 8.2
• HLA-DRB10832 33
• HLA-DRB11408 6.9
• HLA-DRB11409 13

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HLA-DR and Allergy

• Caucasians
• 2 of the variation in specific IgE to Der p I
• 3.5 of the variation in total serum IgE

• Aborigines
• 11 of the variation in specific IgE to HDM
• 27 of the variation of total serum IgE

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FceRI the allergic trigger

• Association to severe disease
• Asthma
• Atopy
• Bronchial Responsiveness

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Beta Chain of High-affinity IgE Receptor
(FceRI-b) Genomic Structure
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FceRI-b and EczemaTDT association with
FceRIb-InRsaI2
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FceRI-b

• Several mechanisms of variation of regulation
• Functional promoter polymorphisms
• Imprinting
• Splice variation
• Multiple polymorphisms

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Linkage Disequilibrium
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LD

• Measured between markers
• D, D, d2
• Measured between phenotypes and markers
• Association
• Case control
• TDT

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LD and Distance
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TCR-a
0
400 kb 800
kb
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FceRI-b LD
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FceRI-b Haplotypes
47 .1.1.2.1.1.1.1.2. 37.5
.1.2.1.2.2.1.2.2. 2.8 .2.1.2.1.1.2.1.2. 2.3
.1.2.2.2.2.1.2.2. 2.0 .1.1.1.1.1.1.1.2. 1.6
.1.1.1.1.1.1.2.1.
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Hidden patterns in the geography of Europe shown
by the first three principal components,
explaining respectively 28, 22, and 11of the
total genetic variation for 95 classical
polymorphisms. The first component is almost
superimposable to the archaeological dates of the
spread of farming from the Middle East
between10,000 and 6,000 years ago. The second
principal component parallels a probable spread
of Uralic people and/or languages to the
northeast of Europe. The third is very similar
to the spread of pastoral nomads (and their
successors) who domesticated the horse in the
steppe towards the end of the farming expansion,
and are believed by some archaeologists and
linguists to have spread most Indo-European
languages to Europe.
Carvalli-Sforza LL, Trends in Genetics 1998 14
60-65
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Y Chromosome Haplotypes
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LD and Testing for Association

• Test multiple polymorphisms
• Be aware of the LD relationships between
  polymorphisms
• Be aware of population differences in
  polymorphism and LD

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Mendelian Disorders

• Nethertons
• Familial hyper-eosinophilia
• Jobs syndrome (hyper IgE)

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LEKTI
R Esnouf, Y Jones
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Nethertons Gene PolymorphismsAssociations in
150 Families With Eczema
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Nethertons Gene

• How does a protease inhibitor affect atopy?
• Many allergens are proteases
• Skin commensals produce proteases
• Mast cells contain proteases
• Proteases are important in immune signalling

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Positional Cloning

• Genetic linkage
• Co-inheritance of disease and a chromosomal region

• Fine mapping
• Linkage
• Association (linkage disequilibrium)

• Gene identification
• Sequence
• Gene expression

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Asthma LinkagesCoincidence With Other Immune
Diseases
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Eczema (Atopic Dermatitis)

• Affects one in seven children in the UK
• 60 of children with severe eczema have asthma
• Substantial morbidity
• 500,000,000 per annum in the UK to treat

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Atopic Dermatitis
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Atopic Dermatitis Psoriasis
1 2 3 4 5 6 7 8
9 10 11 12 13 14 15 16
17 18 19 20 21 22 X Y
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Christiano AM. Frontiers in keratodermas pushing
the envelope. Trends Genet 199713(6)227-33.
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So

• Genes affecting immune disorders are concentrated
  within a few chromosomal regions
• There are clusters of genes with general effects
  on dermal inflammation and immunity
• The atopic component of atopic dermatitis may be
  secondary

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Localisation by Genetic Linkage

• Single gene disorders
• Localisation to within 1,000,000 base pairs of
  DNA
• Gene identification easy
• Complex genetic disorders
• Localisation to within 10-40,000,000 base pairs
  of DNA
• Gene identification difficult

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Linkage Disequilibrium mapping
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• Chromosome 2

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Chromosome 2 Multi-allelic TDT
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Location of Exons in LD Map
LnIgE
Asthma
Ia
IIs
Ib
Ic
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• Chromosome 13

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Chromosome 13Genetic Linkage to Atopy
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Chromosome 13 TDT and QTDT
Maternal effects included in models
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Chromosome 13 contig
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LD Map of Chromosome 13 Atopy Locus
Association to IgE
A
C
B
Aii
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Miriam Moffatt Youming Zhang Andrea
Heinzmann Emiko Noguchi Goncalo Abecasis James
Traherne Mike Hill Mauro DAmato
Bill Musk Alan James John Harper Jean-Pierre
Kinet Sanger Centre Oxagen Ltd